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(l to r) Nao Uchida, Sachie K Ogawa, William Menegas, Mitsuko Watabe-Uchida and Yoh Isogai

Dopamine, originally referred to as a pleasure molecule, is now one of the most well known neurotransmitters. Dopamine neurons are thought to broadcast a teaching signal for reinforcement learning throughout the brain. Dopamine neurons in the midbrain encode reward prediction error, which is the discrepancy between our expectation and reality. This signal potentially guides our behavior to maximize rewards in the future.

In a previous study (Watabe-Uchida et al., 2012), we used a genetically modified rabies virus to label all of the monosynaptic inputs to dopamine neurons. We reasoned that finding the inputs to these neurons would help us understand how they function. We found that many brain areas project directly onto dopamine neurons, but wanted to further refine our map of this circuit.

In our new study, led by Mitsuko Watabe-Uchida, (Menegas et al., 2015), we labeled the inputs to dopamine neurons based on their projection target. The main projection target of midbrain dopamine neurons is the striatum. However, dopamine neurons also project to other brain areas such as the amygdala, habenula, and much of the cortex. If dopamine encodes a teaching signal that guides behavior, then each brain area might improve its “behavior” in parallel to other brain areas. The simplest way of doing this would be for each brain area to send an expectation signal to dopamine neurons and receive an error signal back from that same population.

Instead, we found that most populations of dopamine neurons (defined by their projection targets) have a surprisingly similar distribution of inputs and are not embedded in parallel circuits. So, each brain area probably does not learn independently.

However, we also found that dopamine neurons projecting to the tail of the striatum differ dramatically from other populations. While most dopamine neurons receive many inputs from regions involved in reinforcement learning, addiction, and appetitive behavior (such as the ventral part of the striatum and hypothalamus), dopamine neurons projecting to the tail of the striatum receive inputs preferentially from regions involved in motor function and arousal (such as the globus pallidus, subthalamic nucleus, and zona incerta). This result suggests that dopamine release in the tail of the striatum might have a unique function, while most other dopamine neurons may encode a teaching signal.

This new study (Menegas et al., 2015) used CLARITY, a method for making tissue optically transparent, to allow the brains to be imaged as whole volumes using a light-sheet microscope. These brains were then aligned in 3D so that they could be compared to each other using a standard set of region boundary definitions. This is a technical benchmark for future anatomical studies, demonstrating that intact whole-brain imaging can be used to compare the inputs of different populations of cells with high precision in an automated fashion.

In summary, we pioneered an automated imaging pipeline which helps to lower the hurdle for future systematic anatomy studies, and increase their consistency and efficiency. Using this technique, we uncovered organization of dopamine circuits and found a unique population of dopamine neurons: the tail of striatum-projecting dopamine neurons. What is the function of this group of dopamine neurons? We hope that our study opened the door to further investigation.

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